The current antiretroviral regimens including protease inhibitors are quite efficacious in suppressing viral replication and decreasing morbidity and mortality. However, if adherence is suboptimal, it is presumed that viral titers will rebound and the risk of developing resistant virus increases. Adherence has long been a difficult issue in clinical medicine, and the understanding of adherence to therapy in HIV is limited. Furthermore, randomized clinical trials to improve adherence to therapy have been few, and none have been done in HIV. This project consists of two phases, an observational cohort study and a randomized clinical trial, designed to address the problem of adherence to therapy. The specific aims of Phase I are: 1) to determine the magnitude of the difference in fraction of prescribed doses taken between individuals who do and do not maintain viral titers below the limit of quantification, 2) to assess the relationship between a priori defined adherence summary statistics (adherence descriptor variables) and virological outcomes, and 3) to determine the demographic and psychosocial characteristics of patients that are associated with poor adherence, as defined by the adherence descriptor variables identified in Aims l and 2 to be clinically relevant. Adherence will be monitored using state-of- the-art microelectronic monitoring of pill taking. Phase II is a 2x2 factorial design randomized clinical trial to test whether a beeper based mnemonic aide, a case management intervention or both improve adherence to antiretroviral therapy (Aim 4). The case manager approach is based on social problem solving, as refined by Nezu, Nezu and Perri for the treatment of depression. The mnemonic aide is a beeper located in the microelectronic monitoring device. A secondary aim of this phase is to reassess the results of Aim 2 using the subjects in the randomized clinical trial as a validation cohort (Aim 5). The short-term objectives of this project are to define the clinically relevant adherence summary statistics in HIV therapy and to identify the risk factors for exhibiting poor adherence. The long-term objective is to test two different strategies, one individually targeted (case manager) and the other broad based (mnemonic aide), to determine if these interventions can improve adherence, and ultimately, clinical outcome in HIV.